Multiple sclerosis is a demyelinating and chronic inflammatory disease of the central nervous system. The histopathologic hallmarks of the disease include focal infiltration of both CD4+ and CD8+ T cells together with other inflammatory cells in the white matter and demyelination with evidence of some axonal damage. The myelin proteins thought to be the target of an immune response in multiple sclerosis include myelin basic protein (MBP), proteolipid protein (PLP), myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG).
A variety of therapeutic approaches are now available in humans to treat multiple sclerosis. However, no curative treatments exist for multiple sclerosis. While a number of compounds, including corticosterioids and modified beta interferon, can reduce some symptoms of multiple sclerosis, they have proven to have serious side effects or otherwise been shown to be less than desirable for long term use.
One promising treatment for multiple sclerosis is described in WO 02/077025 which discloses the use of peptide analogs of myelin basic protein (MBP). Compositions comprising these analogs are reportedly able to ameliorate symptoms of MS without excessive side effects. Moreover, use of peptide analogs to myelin constitutive proteins were also shown to be effective in treating the symptoms of experimental allergic encephalomyelitis (EAE), an organ specific immune disorder often used in mice as a model for MS. However, several phase II clinical trials had to be halted due to the poor tolerance of the altered MBP peptide at the dose tested (Bielekova et al., nature medicine, 2000, (6) 10: 1167 et Kappos et al., nature medicine, 2000, (6) 10: 1176).
Another promising treatment for multiple sclerosis is also described in EP0587735. Said treatment is based on the rational that immunologic exposure to a peptide closely resembling an autoreactive TCR fragment should enhance Th2 cells priming/recognition, and thus help to maintain cytokine regulatory control over Th1-mediated inflammation. Clinical trials have demonstrated acceptable safety and tolerability of this treatment by the patients; however, this treatment is only effective on 50% of the immunized patients. US2004/0087018 describes a method for treating multiple sclerosis in a patient in need thereof, comprising administering antigen-specific IL-10 producing cells to said patient together with the soluble antigen, preferably simultaneously.
The inventors surprisingly found that the administration of Tr1 cells directed against a multiple sclerosis-associated antigen, without co-administration of the soluble antigen, dramatically inhibits the development of EAE in immunized mice.
Therefore, the Applicant aim to provide another type of treatment for multiple sclerosis based on the use of Tr1 cells.